Background: Patients with thalassemia major face an extra challenge in the form of nocturnal enuresis. Objective: To evaluate and assess the prevalence and risk factors of nocturnal enuresis in thalassemia major patients. Patients and Methods: Data of this cross-sectional study was gathered from the clinical records in the out-persistent facility of Pediatric Hematology and Oncology Unit, Zagazig clinics. The study recruited 132 children aging 6-18 years. They were submitted to careful history taking including (age, sex, place, protocol of therapy, duration of follow up), thorough clinical examination and laboratory tests included: CBC and reticulocyte count, bilirubin (direct – indirect), hemoglobin electrophoresis test, liver function tests, kidney function tests, random blood sugar, urine analysis, bacterial count in urine and paired serum and urine osmolality. Results: There was statistically significant relation between the age, family history, splenectomy and nocturnal enuresis. There was statistically significant relation between decreasing nocturnal enuresis and regularity of blood transfusion. The ferritin levels were statistically lower in patients with nocturnal enuresis than those without nocturnal enuresis. A statistically significant negative correlation was found between urine osmolality and ferritin levels in patients with nocturnal enuresis. Conclusion: Family background of enuresis and family and social issues have a significant job in the predominance of bedwetting among thalassemia major patients. The predominance of nighttime enuresis in patients with thalassemia significantly declines with expanding age and customary blood transfusion. The rate of bedwetting increments in thalassemia major patients with iron and hemoglobin inadequacy.